Paracetamol (Acetaminophen) use in infants and children was never shown to be safe for neurodevelopment: A systematic review - Preprints.org

 
Paracetamol (Acetaminophen) use in infants and children was never shown to be safe for neurodevelopment: A systematic review - Preprints.org
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 November 2020                         doi:10.20944/preprints202011.0173.v1

                   Paracetamol (Acetaminophen) use in infants and children was never
                      shown to be safe for neurodevelopment: A systematic review

                              Jasmine Cendejas-Hernandez 1, Joshua T. Sarafian 1, Victoria Lawton 1,
                            Antara Palkar 1, Lauren Anderson 1, Vincent Larivière 2, and William Parker 1

                                    1
                                        Department of Surgery, Duke University School of Medicine, Durham, NC, USA
                            2
                                École de bibliothéconomie et des sciences de l'information, Université de Montréal, Canada

             Correspondence: William Parker, Ph.D.
                                     Department of Surgery
                                     Duke University Medical Center, Box 2605
                                     Phone 919-681-3886
                                     E-mail: William.Parker@Duke.edu

             Running Title: Paracetamol safety and neurodevelopment
             Keywords: behavior, neurodevelopment, infant, child, autism

             Abstract
             Although widely believed to be safe for use in infants and children when used as directed, increasing evidence
             indicates that early life exposure to paracetamol (acetaminophen) may cause long-term neurodevelopmental
             problems. Further, recent studies in animal models demonstrate that cognitive development is exquisitely sensitive
             to paracetamol exposure during early development. In this study, evidence for the claim that paracetamol is safe was
             evaluated using a systematic literature search. Publications on PubMed between 1974 and 2017 that contained the
             keywords “infant” and either “paracetamol” or “acetaminophen” were considered. Of those initial 3096 papers, 218
             were identified that made claims that paracetamol was safe for use with infants or children. Of these, a total of 103
             papers were identified as sources of authority for the safety claim, and 36 of those contained actual experiments
             designed to test safety. The 36 experiments described had a median follow-up time of 24 hours, and none monitored
             neurodevelopment. Further, no trial considered total exposure to drug since birth, eliminating the possibility that the
             effects of drug exposure on long-term neurodevelopment could be accurately assessed. On the other hand, abundant
             and sufficient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or
             children when used as directed.

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             Introduction

                      Hundreds of reports claim emphatically that, when used as directed, paracetamol (acetaminophen) is safe
             for use in babies and in children. However, mounting evidence points toward the view that paracetamol exposure
             during early development can have an adverse effect on neurodevelopment, even when used as directed. For
             example, in a recent review [1], eight studies supporting a link between prenatal paracetamol exposure and
             neurodevelopmental problems were identified [2-9]. In the three years since that review, five additional studies have
             confirmed this same relationship, three of which have used data from the Norwegian Mother and Child Cohort
             Study [10-14]. Although exposure to paracetamol in utero is associated with neurodevelopmental problems, even
             after consideration of potentially confounding factors, the effects are typically small and the amount of paracetamol
             required to yield the effect is greater than the amount typically used by average individuals. For example, after
             adjusting for potential confounders such as parental education level, use of vitamin supplements, parental BMI,
             smoking, and use of other drugs, Skovlund and colleagues found a weak yet significant association between prenatal
             exposure to paracetamol and mother-reported communication skills: the chances of being in a lower development
             category increased with increasing periods of prenatal paracetamol use but not prenatal opioid use [10]. In another
             example, using propensity score matching, Vlenterie and colleagues found that 28 or more days of paracetamol use
             during pregnancy was associated with a modestly increased risk of delayed motor milestone attainment (OR: 1.35,
             95% CI 1.07–1.70) by children at 18 months [11].
                      Evidence points toward a higher risk of paracetamol-induced neurodevelopmental disorders when exposure
             occurs after birth as compared to in utero. Studies using laboratory rodents demonstrate that exposure to near
             therapeutic doses of paracetamol during the first days of life induces profound, long-term neurological changes [15,
             16], whereas somewhat higher doses are required to induce permanent neurological damage during pregnancy [17].
             These laboratory studies demonstrate that the target organ for toxicity in neonates is the central nervous system, not
             the liver, and demonstrate that if paracetamol had been tested using current guidelines, it would never have been
             approved for use in children. More concerning are observations in children indicating that paracetamol is not safe
             for neurodevelopment. The 2008 study which first raised a red flag regarding the safety of paracetamol during
             neurodevelopment found a greater than 20-fold risk of regressive autism with paracetamol use during childhood
             [18]. Although this relatively small study did not attract enough interest to promote larger studies, other lines of
             evidence support the view that paracetamol exposure during early life can lead to neurodevelopmental disorders. For
             example, a startling 2-fold greater incidence of infantile autism in circumcised boys compared to non-circumcised
             boys [19] can be readily explained by potentially negative impacts of paracetamol exposure during and following
             the circumcision procedure [1]. Sadly, the widely held and entrenched belief that vaccines induce autism [20, 21]
             may be yet another result of the impact of paracetamol on neurodevelopment in combination with widespread use of
             the drug during vaccination [1].
                      With the above concerns in mind, a systematic evaluation of the peer-reviewed literature was initiated to
             address the question of why paracetamol is widely believed to be safe for use during early development. All papers
             published between 1974 and 2017 that contained the keywords “infant” and either “paracetamol” or

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             “acetaminophen” were considered. All papers which made claims that paracetamol or acetaminophen is safe for use
             in infants or children were identified, and the justification for this claim was critically evaluated.

             Methods

                 As a first step in understanding why paracetamol is thought to be safe during early development, all titles and
             abstracts in the PubMed® Database with keywords “infant” and “acetaminophen or paracetamol” published between
             1974 and 2017 were identified. The term “infant” rather than “child” was selected because (a) the number of papers
             with the term “child” was prohibitively large, and (b) the focus of the study was intended to be on drug exposure
             during early development, from birth to age approximately 6 years, not individuals up to the age of 17 years. In all
             cases, the terms paracetamol and acetaminophen were taken to be synonymous, and no distinctions were made.

                 In the second step, two coauthors (JCH and JTS) independently screened all titles and abstracts. In this step,
             articles that could not be obtained in English and all articles not describing use of paracetamol in humans were
             eliminated from the study. Based on titles and abstracts (if available), articles were tagged which were deemed likely
             to make claims regarding the safety of acetaminophen use in infants and children between birth and age 6 years.

                 In the third step, two coauthors (JCH and JTS), continuing to work independently, examined full texts of all
             tagged titles and abstracts. Texts were examined for the following three assertions:
                 (a) paracetamol use is “safe” in children or infants
                 (b) paracetamol is the “drug of choice” in children or infants
                 (c) paracetamol use is “recommended” for children or infants

                 In cases where the terms “drug of choice” or “recommended” were used, the context was considered. In some
             cases, particularly in manuscripts expressing caution regarding the use of paracetamol, these terms were not taken to
             imply safety, but rather were taken to be an indicator of the common acceptance of the drug. These articles were
             excluded from the study. Based on this approach, articles were tagged that were considered to have made safely
             claims regarding the use of paracetamol in infants or children younger than 6 years old.
                 Still working independently, two coauthors (JCH and JTS) evaluated each manuscript making a claim of safety,
             determining the source of authority for the stated claim. If no literature was cited to support the claim, this was
             documented. In cases where the source that was cited contained another citation, that secondary reference was
             obtained and evaluated. This process continued as needed until an original source or sources describing an actual
             demonstration of safety was identified. An example of the results of this process is shown in Figure 1.

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             Figure 1. Flow diagram illustrating connections between articles claiming that paracetamol use is safe for infants or
             children when used as directed. In this example, the citations in a paper by Temple and colleagues in 2017 [25] are
             assessed. Articles describing new experiments designed to test safety of paracetamol or which contain claims of
             safety without citation are included in Table 2 and are indicated by a check mark. Articles shown in the diagram
             which do not describe experiments designed to test safety of paracetamol and which cite other articles as a source
             for claims of safety [23, 26, 27, 134] are not included in Table 2 and are not indicted by a check in the diagram.

                 In the fourth step, any discrepancies between the analyses provided by coauthors JCH and JTS were arbitrated
             by coauthor WP. In the fifth step, articles upon which safety claims were based were compiled. Finally, articles
             upon which safety claims were based and which contained experiments designed to assess safety were evaluated.
             For each experiment described, the study group, endpoints measured, and follow-up time were evaluated.

             Results

                 An overview of results from a systematic search for studies demonstrating safety of paracetamol use in infants
             and children is shown in Table 1. The initial Medline search provided 3096 articles that contained the terms infant
             and either paracetamol or acetaminophen that were published between 1974 and 2017. From these articles, 467 were
             selected for assessment based on likelihood of safety claims regarding use of paracetamol in infants or children. Of
             these 467 articles, 218 made safety claims regarding the use of paracetamol in infants or children. During this phase
             of the study, numerous articles were identified which either claimed or demonstrated that paracetamol use, even at
             doses beyond the recommended dose, does not generally cause long-term liver damage in infants or children. Any
             claims of safety for liver function were not evaluated in detail and were not considered in this study. Only general
             claims of safety were assessed.

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             Table 1. Number of citations identified in the systematic search during each step of the study. Numbers are provided
             for both analysts performing the work (JCH and JTS). The overlap is the number of citations that were the same
             between the two analysts. *Numbers in parentheses indicated the number of citations in which both analysts
             identified the same citation, but not the same source or sources as the authority for claims of safety.

                                             Step                                    JCH          Overlap          JTS        Total
              1. Medline (APAP + infant)                                                                                   3096
              2. Safety claim, first step                                           310        193                350      467
              3. Safety claim, second step                                          189        144 (53*)          189      234
              4. Safety claim, final                                                173        128 (37*)          173      218
              5. Sources attributed to safety claim                                                                        103
              6. Sources with experiments attributed to safety claim                                                       36
                 Of the 218 articles making claims that paracetamol use in infants or children is safe, half (114) provided no
             citation. The other half (114) of the articles cited additional articles as evidence that paracetamol is safe in infants or
             children. Cited articles were carefully evaluated as described in the methods. In some cases, those “primary” cited
             articles did not make original claims of safety, but rather cited additional (“secondary”) articles. In cases where a
             primary article cited another article, the primary article was not considered to have made an original claim of safety,
             and was not evaluated further. An example of the results of this process is shown in Figure 1. Both primary articles
             and secondary (and tertiary, etc) articles attributed with claims of the safety of paracetamol use in infants or children
             were compiled and are shown in Table 2. In total, 103 articles were identified which were cited as containing
             original claims that paracetamol use in infants or children is safe when used as directed.

                 Table 2. Sources cited as stating that acetaminophen is safe for infants or children when used as directed. *This
                 article is cited as “Renn E. The antipyretic use of paracetamol versus ibuprofen in a pediatric care setting.
                 Physical Therapy. 2000;25:395-397.” This reference does not apparently exist: The volume number
                 corresponding to the year 2000 for the journal Physical Therapy is 80, not 25. We were unable to determine
                 what actual article it may have originally referred to. **The Canadian Pediatric Society paper from 1998 was
                 mis-cited as being from 2000 in one instance. *** This article, cited as Kehlet and Werner (2003) from the
                 journal Drugs, Volume 63, pp 15-22 (Spec no 2), does not exist on the journal’s website for unknown reasons.

                                                                                        Outcome
               Sources cited for safety of paracetamol         Study subjects       measures related         Duration of        Times
                in children or infants: study number,                              to safety or safety       monitoring         cited
                           year, and design                                           claims made.
              1. 1999: Double-blind clinical trial with       9,127 children       “Serious adverse        4 weeks             13
              three treatments, one of paracetamol and        treated with         clinical events”
              two different concentrations of ibuprofen       paracetamol;         requiring
              given for fever [22]                            median age is        hospitalization:
                                                              14 months            gastrointestinal
                                                                                   bleeding, renal
                                                                                   failure,
                                                                                   anaphylaxis,
                                                                                   Reye’s syndrome,
                                                                                   asthma,
                                                                                   bronchiolitis, and
                                                                                   vomiting/gastritis

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              2. 1997: Double-blind, randomized, three-    80 children were   Monitoring by          2 hours: all     9
              way crossover study with three treatments,   treated with       parents for            patients
              one each of paracetamol, ibuprofen, and      paracetamol,       “adverse events”:      received
              placebo given by parents for headache.       age range          nausea, vomiting,      paracetamol at
              Each child with three migraine attacks was   approximately 4    and gastric pain       some point, so
              treated in random order with single oral     to 16 years                               long-term
              doses of the study drugs [34]                                                          monitoring was
                                                                                                     not feasible.
              3. 1978: Editorial describing current        NA: Editorial      Claims:                NA: Editorial    8
              practice with analgesic use in children                         “anticipated liver
              [35]                                                            damage is not
                                                                              observed” based
                                                                              on personal
                                                                              experience and
                                                                              interactions with
                                                                              other clinicians
              4. 2001: Review describing analgesic use     NA: Review         Claims: “40-year       NA: Review       8
              in children [36]                                                safety record in
                                                                              children” without
                                                                              citation
              5. 1978: Review describing antipyretic       NA: Review         Claims: “relatively    NA: Review       7
              therapy in febrile children [37]                                free of adverse
                                                                              reactions” without
                                                                              citation and 9
                                                                              citations provided
                                                                              for the statement
                                                                              that hepatotoxicity
                                                                              from paracetamol
                                                                              in children is "very
                                                                              low compared with
                                                                              that seen in adults"
              6. 2000: Renn, 2000                          NA: Erroneous      NA: Erroneous          NA: Erroneous    7
              Erroneous citation*                          citation           citation               citation
              7. 2011: Report describing current           NA: Report         Claims: “generally     NA: Report       7
              recommended practice [38]                                       regarded as safe”
                                                                              without citation.
                                                                              Lesko (1999) is
                                                                              cited for equivalent
                                                                              safety between
                                                                              ibuprofen and
                                                                              paracetamol.
              8. 1983: Review describing pediatric         NA: Review         Claims: “one of the    NA: Review       6
              dosing of paracetamol [39]                                      safest” without
                                                                              citation
              9. 1995: Double-blind clinical trial with    28,130 children    Serious events         4 weeks          6
              three treatments, one of paracetamol and     treated with       defined as
              two of different concentrations ibuprofen    paracetamol;       hospitalization for
              given for fever [40]                         median age is      acute
                                                           40 months          gastrointestinal
                                                                              bleeding, acute
                                                                              renal failure, or
                                                                              anaphylaxis.
              10. 1998: Practice guidelines** [41]         NA: Practice       Claims: “As            NA: Practice     5
                                                           guidelines         demonstrated by        guidelines
                                                                              the numerous

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                                                                             prospective clinical
                                                                             studies”,
                                                                             paracetamol is
                                                                             “remarkably safe
                                                                             in therapeutic
                                                                             doses”, without
                                                                             citation.
              11. 1972: Double-blind study with two        39 children       Unspecified            6 hours         5
              treatments, one each of aspirin and          treated with      “complications or
              paracetamol, given for antipyretic effect    paracetamol,      side effects”
              [29]                                         age 6 months to
                                                           6 years
              12. 1977: Clinical guidelines for use,       NA: Clinical      Considered to have     NA: Clinical    4
              predominantly focused on aspirin, but also   guidelines        a “wide range of       guidelines
              including paracetamol. [28]                                    safety” based on
                                                                             “the large doses of
                                                                             paracetamol
                                                                             required to evoke
                                                                             toxic reactions” in
                                                                             laboratory animals.
                                                                             In addition,
                                                                             considered “safe
                                                                             and effective when
                                                                             used as directed”,
                                                                             with two studies
                                                                             cited [29, 30]
              13. 1978: Commentary on paracetamol          NA:               Claims: “safe and      NA:             4
              use [42]                                     Commentary        effective analgesic    Commentary
                                                                             and antipyretic in
                                                                             usual therapeutic
                                                                             dosage” without
                                                                             citation.
              14. 1978: Review comparing aspirin’s and     NA: Review        Claims: “the           NA: Review      4
              paracetamol’s antipyretic and analgesic                        choice of agents
              activity [43]                                                  for antipyresis in
                                                                             clinical practice
                                                                             has been narrowed
                                                                             to aspirin and
                                                                             paracetamol”
                                                                             without citation.
              15. 1996: Review of paracetamol liver        NA: Review        Makes no general       NA: Review      4
              toxicity in children under the age of 6                        safety claim,
              years [44]                                                     although extensive
                                                                             references are
                                                                             provided showing
                                                                             that paracetamol
                                                                             does not cause
                                                                             long-term damages
                                                                             to infants’ livers.
              16. 1997: Double-blind clinical trial with   97 children       Renal function as      4 weeks         4
              three treatments, one of paracetamol and     treated with      indicated by blood
              two different concentrations of ibuprofen    paracetamol;      urea nitrogen
              given for fever [45]                         median age is     (BUN) and
                                                           29 months         creatinine levels.

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              17. 1972: Clinical study with three          80 children         No outcome             6 hours or less   4
              treatments, one each of aspirin,             treated with        measures
              paracetamol, and a combination of the two    paracetamol,        specified.
              given for fever [30]                         age 6 months to
                                                           5 years
              18. 2005: Pharmacokinetic study.             NA:                 No safety              NA:               3
              [46]                                         Pharmacokinetic     outcomes reported.     Pharmacokineti
                                                           study               No safety claims       c study
                                                                               made.
              19. 2011: Randomized open-label study        75 patients total   Changes in liver       48 hours          3
              with two dosing regimens of intravenous      were treated        enzymes, changes
              paracetamol given for analgesic or           with                in vital signs, and
              antipyretic effect.                          paracetamol, 3      reported or
              [47] Intravenous paracetamol contains        neonates, 25        observed adverse
              cysteine, an antidote for paracetamol        infants, 25         drug effects, which
              poisoning. The antidote is not present in    children, and 22    included the
              the oral medication.                         adolescents         following: anemia,
                                                                               constipation,
                                                                               nausea, vomiting,
                                                                               face edema,
                                                                               pyrexia,
                                                                               hypokalemia,
                                                                               hypomagnesemia,
                                                                               hypophosphatemia,
                                                                               agitation,
                                                                               atelectasis, pleural
                                                                               effusion,
                                                                               pulmonary edema,
                                                                               stridor, wheezing,
                                                                               periorbital edema,
                                                                               and pruritus
              20. 1973: Review describing precautions      NA: Review          Makes no safety        NA: Review        2
              with paracetamol use                                             claim with respect
              [48]                                                             to pediatric use.
              21. 1981: Review comparing efficacy of       NA: Review          Claims: a “high        NA: Review        2
              aspirin and paracetamol in fever reduction                       degree of safety” at
              in children                                                      therapeutic doses
              [49]                                                             without citation.
              22. 1992: Pharmacokinetic study in adults    NA:                 NA: study in adults    NA:               2
              aged 21-25 years [50]                        Pharmacokinetic                            Pharmacokineti
                                                           study                                      c study
              23. 1993: Review [51]                        NA: Review          Claims: “Recent        NA: Review        2
                                                                               data have
                                                                               supported the
                                                                               relative safety (and
                                                                               efficiency) of
                                                                               paracetamol in
                                                                               newborn infants”
                                                                               without citation.
              24. 1996: Double-blind study with two        47 children were    Extensive              36 hours          2
              treatments, one of each ibuprofen and        treated with        assessment of
              paracetamol, given for fever [52]            paracetamol,        adverse events.
                                                           age 0.2 to 9.4      Claims: “majority
                                                           years; median       of adverse events
                                                           age is 1.6 years    had a doubtful or

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                                                                               no relationship the
                                                                               treatment, and
                                                                               most were
                                                                               considered mild.”
              25. 1997: Computer simulation used to        NA: Computer        No safety claims        NA: Computer      2
              predict dosing needed to achieve desired     simulation          made.                   simulation
              concentration of drug in plasma [53]
              26. 1997: Pharmacokinetic study.             NA:                 No safety               NA:               2
              [54]                                         Pharmacokinetic     outcomes reported.      Pharmacokineti
                                                           study.              Claims:                 c study.
                                                                               “Commonly used
                                                                               in children because
                                                                               of its (efficacy
                                                                               and) safety”
                                                                               without citation.
              27. 1999: Pharmacokinetic study with a       28 preterm          No safety               Up to 12 hours    2
              single rectal dose of paracetamol [55]       neonates, 2 days    outcomes stated.
                                                           after birth         Claimed: “safe”
              28. 2007: Comparison of efficacy between     150 patients        Monitoring for          3 days            2
              paracetamol and ibuprofen. First phase       treated with        “adverse events,”
              was a single dose, double-blind              paracetamol,        three of which
              administered in the clinic, followed by an   age range           were infections,
              open-label phase administered at home for    approximately       gastrointestinal
              the second and subsequent doses. [56]        0.40 to 11 years;   disorders, and
                                                           average age is      respiratory
                                                           3.71 years          disorders.
              29. 2008: Retrospective study using data     149 neonates        Hepatic enzyme          48 hours          2
              collected in neonates treated with           total, median       profiles including
              intravenous paracetamol.                     postmenstrual       ALT, AST, and
              [57]                                         age 38 weeks        GGT
                                                           and median
                                                           postnatal age is
                                                           5 days
              30. 2011: Review describing NSAIDs and       NA: Review          Makes no safety         NA: Review        2
              paracetamol and their roles in reducing                          claim.
              side-effects after surgery [58]
              31. 2013: Review describing dosing and       NA: Review          Claims: “dosing         NA: Review        2
              antipyretic efficacy of paracetamol [59]                         range is well
                                                                               tolerated in
                                                                               children” without
                                                                               citation.
              32. 1965. Pharmacology reference book        NA: Review          Pediatric dose          NA: Review        1
              [60]                                                             stated without
                                                                               citation, and
                                                                               without further
                                                                               discussion of
                                                                               pediatric use.
                                                                               Makes no safety
                                                                               claim.
              33. 1967: Clinical comparison of a single    50 infants          Unspecified             6 hours           1
              dose of paracetamol, aspirin, and            treated with        “undesirable
              salicylamide [61]                            paracetamol, up     effects” not
                                                           to 48 months        observed
                                                           old

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              34. 1978: Review describing the             NA: Review         Does not discuss       NA: Review         1
              pathophysiology of aspirin overdosage                          paracetamol.
              [62]                                                           Makes no safety
                                                                             claims
              35: 1982. Monitoring of drug use by the     1,158 children,    Adverse events not     NA: No follow-     1
              Pediatric Drug Surveillance Program [63]    up to age 16,      reported. Makes no     up conducted
                                                          received           safety claim
                                                          paracetamol
              36. 1982: An abstract [64] cited by Ragg,   Not determined     Not determined         Not determined     1
              1997 [65]
              37. 1984: Prospective study observing       132 children,      No side effects        During inpatient   1
              adverse drug reactions in pediatric         age not            observed. No           stay: time not
              inpatients. [66]                            specified,         safety claims          specified.
                                                          received an        made.
                                                          antipyretic or
                                                          analgesics while
                                                          hospitalized
                                                          (paracetamol
                                                          not mentioned)
              38. 1989: Editorial comparing ibuprofen     NA: Editorial      Claims:                NA: Editorial      1
              and paracetamol [67]                                           “therapeutic doses
                                                                             of either drug
                                                                             [ibuprofen and
                                                                             paracetamol] cause
                                                                             no discernable
                                                                             adverse effects”
                                                                             without citation.
              39. 1989: Review assessing pain in          NA: Review         Claims: “Recent        NA: Review         1
              neonates and the approaches to                                 data have
              postoperative analgesia                                        supported the
              [68]                                                           relative safety and
                                                                             analgesic efficacy
                                                                             of paracetamol in
                                                                             newborn infants”
                                                                             without citation.
              40. 1990: Pharmacology reference book       NA: Review         Claims: “usually       NA: Review         1
              [69]                                                           well tolerated”
                                                                             without citation,
                                                                             but use in pediatric
                                                                             populations is not
                                                                             discussed.
              41. 1991: Review describing paracetamol     NA: Review         Makes no safety        NA: Review         1
              hepatotoxicity and poisoning in children                       claim
              [70]
              42. 1992: Review describing the             NA: Review         Claims:                NA: Review         1
              hepatotoxicity of non-steroidal anti-                          Paracetamol is
              inflammatory drugs [71]                                        “normally very
                                                                             safe when used
                                                                             properly” although
                                                                             this statement does
                                                                             not necessarily
                                                                             refer to pediatric
                                                                             use
              43. 1992: Randomized, double-blind,         16 children        Adverse events         24 to 48 hours     1
              multidose, parallel-group, variable         treated with       included headache,

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              duration clinical trial with three different   paracetamol;        gastrointestinal
              concentrations of ibuprofen and one of         average age is      effects, sweating,
              paracetamol given for pediatric fever [72]     5.2 years           hypothermia,
                                                                                 abdominal pain,
                                                                                 agitation,
                                                                                 nervousness, and
                                                                                 adverse
                                                                                 experiences related
                                                                                 to the respiratory
                                                                                 system.
              44. 1994: Textbook [73] cited by Wilson,       NA: Textbook        Not determined         NA: Textbook    1
              1995. [74]
              45. 1996: Double-blind study with two          100 children        Liver enzymes          24 hours        1
              treatments, paracetamol and placebo given      were treated        determined by
              for postoperative pain [75]                    with                blood samples.
                                                             paracetamol,
                                                             age 3 to 14
                                                             years
              46. 1996: Randomized study with two            28 children, age    Outcome measures       240 minutes     1
              treatment groups, one of which received        2 to 8 years        included pain
              paracetamol preoperatively and the other                           scores and the need
              postoperatively [76]                                               for rescue
                                                                                 analgesics
              47. 1997: Double-blind, multicenter study      56 children         Changes in             6 hours         1
              with two treatments, one each of ibuprofen     treated with        temperature. Only
              and paracetamol, given for fever [77]          paracetamol,        side effect reported
                                                             age 8 months to     was vomiting.
                                                             11 years;
                                                             average age is
                                                             4.2 years
              48. 1999: Randomized, double-blind,            90 children         Postoperative pain     24 hours        1
              placebo-controlled study with four             treated with        was evaluated by
              different concentrations of paracetamol        paracetamol,        behavioral
              given after induction of anesthesia [78]       age 1 to 7 years    assessment and
                                                                                 physiologic
                                                                                 measurement.
                                                                                 Only side effects
                                                                                 reported were
                                                                                 postoperative
                                                                                 nausea and
                                                                                 vomiting
              49. 1999: Clinical trial examining the         10 infants, up to   Adverse events not     First 2 days    1
              efficacy and pharmacokinetics of               the age of 2        reported. Claims:      after birth
              paracetamol in term infants (multiple-         days                “paracetamol can
              dose) [79]                                                         be administered
                                                                                 safely to neonates
                                                                                 on the first day of
                                                                                 life”
              50. 2000: Review describing non-opioid         NA: Review          Claims: rectal         NA: Review      1
              drugs for treatment of postoperative pain                          paracetamol
              [80]                                                               “seems safe in
                                                                                 children” without
                                                                                 citation.

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              51. 2000: Pharmacokinetic study of            21 children, age   No sign of adverse      Variable, from 1   1
              postoperative, repeated dosing of rectal      9 weeks to 11      effects observed.       to 5 days
              paracetamol [81]                              years              Claims:
                                                                               Paracetamol has
                                                                               gained wide
                                                                               acceptance as a
                                                                               simple and safe
                                                                               antipyretic and
                                                                               analgesic in
                                                                               children”, without
                                                                               citation.
              52. 2000: Observational study of calls to a   1,019 children     Parent’s report of      72 hours           1
              poison center to evaluate pediatric           up to the age of   signs of
              paracetamol exposures [82]                    7 years            hepatotoxicity.
              53. 2000: Review of paracetamol’s             NA: Review         Claims:                 NA: Review         1
              history, present and future [83]                                 paracetamol is an
                                                                               “effective and
                                                                               remarkably safe
                                                                               drug when used
                                                                               properly” without
                                                                               citation
              54. 2000: Randomized, double-blind study      24 children        Outcome measures        3 days             1
              with two treatments, one each of              treated with       used were pain
              diclofenac and paracetamol for                paracetamol,       scores and relief of
              postoperative analgesia [84]                  age 5 to 15        pain or dysphagia.
                                                            years; median      Only side effects
                                                            age is 10 years    reported were
                                                                               nausea and
                                                                               vomiting.
              55. 2000: Integrated Management of            NA: Review         Makes no safety         NA: Review         1
              Childhood Illness handbook by the World                          claims
              Health Organization [85]
              56. 2000: Randomized, double-blind,           120 patients,      Disorientation,         8 to 10 hours      1
              multicenter study comparing paracetamol       age 2 to 11        extreme irritability,
              controlled-release sprinkles and              years              and confusion
              paracetamol immediate-release elixir in                          were the only
              febrile children [86]                                            adverse events
                                                                               recorded.
              57. 2000: Guide to pediatric medication       NA: Review         Claims: “Usually        NA: Review         1
              and nutrition [87]                                               well tolerated
                                                                               when used as
                                                                               directed”, without
                                                                               citation.
              58. 2001: Review describing treatment         NA: Review         Claims: “generally      NA: Review         1
              with paracetamol in infants [88]                                 considered a safe
                                                                               drug” without
                                                                               citation but warns
                                                                               of potential
                                                                               toxicity with
                                                                               glutathione
                                                                               depletion.
              59. 2001Literature review describing          NA: Review         Claims:                 NA: Review         1
              perioperative use of high-dose of rectal                         “administration of
              paracetamol [89]                                                 high-dose rectal
                                                                               paracetamol in the

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                                                                             perioperative
                                                                             period appears to
                                                                             be safe” without
                                                                             citation.
              60. 2001: Review describing paracetamol      NA: Review        Claims: safety          NA: Review        1
              toxicity in children [90]                                      based on NAPQI
                                                                             production and
                                                                             glutathione levels
                                                                             without citation.
              61. 2001: Review describing the              NA: Review        Makes no safety         NA: Review        1
              neurobiology of pain [91]                                      claim
              62. 2001: Randomized, stratified, placebo-   NA: minimum       NA: minimum age         NA: minimum       1
              controlled, single-dose, double-blind,       age 16 years,     16 years, average       age 16 years,
              triple-dummy, single-center, parallel-       average age       age 22.2 years          average age
              group study with four treatments, one each   22.2 years                                22.2 years
              of ibuprofen, ketoprofen, paracetamol, and
              placebo given for postoperative dental
              pain [92]
              63. 2001: Blinded study conducted to         40 patients,      Paracetamol             24 hours          1
              observe the analgesic efficacy of rectal     average age is    plasma
              and oral paracetamol in two separate         10.3 years        concentrations and
              groups in children after craniofacial                          pain scores. Only
              surgery                                                        side effect reported
              [93]                                                           was vomiting.
                                                                             Makes no safety
                                                                             claims.
              64. 2002: Review comparing the effects of    NA: Review        Claims: “low            NA: Review        1
              paracetamol, NSAIDs or their                                   incidence of
              combination in postoperative pain                              adverse effects”
              management [94]                                                without citation
              65. 2002: Literature review describing       NA: Review        Claims: “Both           NA: Review        1
              paracetamol and ibuprofen use for fever                        drugs appeared
              treatment in children [95]                                     well tolerated and
                                                                             no evidence of
                                                                             difference in short-
                                                                             term adverse
                                                                             effects was
                                                                             observed” without
                                                                             citation
              66. 2003: Editorial describing use of        NA: Editorial     Claims:                 NA: Editorial     1
              antipyretics [96]                                              paracetamol is
                                                                             “traditional(ly)
                                                                             considered to be
                                                                             safe based on (a)
                                                                             large clinical
                                                                             experience over (a)
                                                                             long time” without
                                                                             citation.
              67. 2003: Erroneous or out of print          NA: Erroneous     NA: Erroneous or        NA: Erroneous     1
              citation*** [97]                             or out of print   out of print citation   or out of print
                                                           citation                                  citation
              68. 2003: Review describing anti-            NA: Review        Claims:                 NA: Review        1
              inflammatory agents and paracetamol in                         “paracetamol
              neonates [98]                                                  remains the drug of
                                                                             choice for

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                                                                               antipyresis in
                                                                               neonates” and “the
                                                                               adverse effect of
                                                                               paracetamol is
                                                                               more favorable”
                                                                               without citation
              69. 2003: Randomized, double-blind,          80 children         Adverse events         All children        1
              placebo-controlled study with four           treated with        defined as             were kept in the
              treatments groups, ibuprofen, paracetamol,   paracetamol,        retching, vomiting,    PACU for 1.5
              a combination of the two, and placebo.       age 1 to 6 years;   abdominal pain,        hours. The
              The purpose was to observe the analgesic     average age is      and dizziness          parents of the
              efficacy of each treatment [99]              2.7 years                                  children were
                                                                                                      asked to record
                                                                                                      the well-being
                                                                                                      of their child
                                                                                                      until 24 hours
                                                                                                      after anesthesia.
              70. 2004: Pharmacokinetic study with a       30 neonates, 24     Liver enzymes          10 hours            1
              single intravenous dose of propacetamol      hours after birth   determined by
              [100]                                                            blood samples.
              71. 2004: Systematic review assessing the    NA: Review          Makes no safety        NA: Review          1
              prevalence of aspirin induced asthma in                          claim with respect
              adults and children and other issues                             to pediatric use.
              related to the syndrome [101]
              72. 2005: Review describing                  NA: Review          Claims:                NA: Review          1
              paracetamol’s tolerability profile [102]                         “Paracetamol is a
                                                                               very well tolerated
                                                                               drug at therapeutic
                                                                               doses” without
                                                                               citation, although
                                                                               this statement does
                                                                               not necessarily
                                                                               refer to pediatric
                                                                               use.
              73. 2005: Randomized, double-blind study     25 children         Agitation in           24 hours            1
              with three treatments, one each of           treated with        recovery measured
              ibuprofen, paracetamol, and placebo given    paracetamol,        using Oucher’s
              before surgery [103]                         age 3 to 12         scale
                                                           years
              74. 2005: Evaluation of pain management      37 children, age    Evaluation of          16 to 20 hours      1
              guidelines for tonsillectomy [104]           5-11 years.         nausea and
                                                                               vomiting.
              75. 2006: Practice guidelines [105]          NA: Practice        Makes no safety        NA: Practice        1
                                                           guidelines          claim                  guidelines
              76. 2006: Practice guideline to assist       NA: Guidelines      Makes no safety        NA: Guidelines      1
              poison center personnel with management                          claim
              of paracetamol poisoning [106]
              77-79. 2004-2010: Three textbooks [107-      NA: Textbooks       Not determined         NA: Textbooks       1
              109] cited by Karbasi and colleagues
              [110]
              80. 2007: Review describing paracetamol      NA: Review          Claims: “an            NA: Review          1
              safety and hepatotoxicity [111]                                  excellent overall
                                                                               safety record” with
                                                                               infants and

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                                                                              children without
                                                                              citation
              81. 2007. Open-label, single-sequence,      NA: study in        NA: study in adults     NA: study in      1
              multiple-dose study with intravenous        adults                                      adults
              paracetamol in adults [112]
              82. 2007: Randomized double-blind           103 children        Outcome measures        6 hours           1
              placebo-controlled study with paracetamol   treated with        included fever
              given for fever [113]                       paracetamol,        clearance time, rate
                                                          age 6 months to     of fall of
                                                          6 years; average    temperature,
                                                          age is 26.1         percent reduction
                                                          months              of temperature,
                                                                              proportion of
                                                                              afebrile children,
                                                                              symptomatic
                                                                              improvement and
                                                                              clinical and
                                                                              biochemical
                                                                              adverse effects.
                                                                              Claims:
                                                                              “considered to be a
                                                                              safe drug at
                                                                              therapeutic levels.”
              83. 2007: Randomized, double-blind,         30 children         Need for                Minimum of 2      1
              placebo-controlled study with three         treated with        postoperative           hours
              treatments, one each of naproxen,           paracetamol,        rescue fentanyl and
              paracetamol, and placebo before the         age 1 to 6 years,   the incidence of
              induction of anethesia [114]                average age is      postoperative
                                                          1.3 years           nausea and
                                                                              vomiting.
              84. 2007: Study with zolmitriptan nasal     NA: study not       NA: study not           NA: study not     1
              spray, not paracetamol [115]                involving           involving               involving
                                                          paracetamol         paracetamol             paracetamol
              85. 2007: Guidelines for assessment and     NA: Clinical        Makes no safety         NA: Clinical      1
              initial management of fever in children     guidelines          claim                   guidelines
              younger than 5 years [116]
              86. 2007: Review describing systemic        NA: Review          Claims: “when the       NA: Review        1
              analgesics for children [117]                                   maximum daily
                                                                              dose of
                                                                              paracetamol is
                                                                              observed it is well
                                                                              tolerated” without
                                                                              citation
              87. 2009: Comparative study with three      112 children        Children were           Up to 48 hours    1
              treatments: paracetamol, ketoprofen, and    were treated        monitored without
              ibuprofen given for fever [118]             with                observation of
                                                          paracetamol,        drug-related side
                                                          average age         effects. Makes no
                                                          about 4 years       safety claim
                                                          old.
              88. Randomized, controlled trial in which   29 infants were     Did not report any      48 hours          1
              patients received either paracetamol or     treated with        adverse events.
              placebo for postoperative pain [119]        paracetamol,        Measured the
                                                          age 0-2 months      efficacy of

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                                                                                  paracetamol, not
                                                                                  safety.
              89. 2009: Review describing the Italian         NA: Review          Claims:                NA: Review        1
              Pediatric Society guidelines on the                                 paracetamol is
              management of fever in children [120]                               “generally well
                                                                                  tolerated” without
                                                                                  citation.
              90. 2009: Review describing drugs of            NA: Review          Makes no safety        NA: Review        1
              choice for sedation and analgesia in the                            claims
              NICU [121]
              91. 2009: Review describing the peri-           NA: Review          Claims:                NA: Review        1
              operative use of paracetamol [122]                                  paracetamol is a
                                                                                  “safe, well-
                                                                                  tolerated drug with
                                                                                  proven efficacy”
                                                                                  without citation.
              92. 2009: Systematic review of the clinical     NA: Review          Makes no safety        NA: Review        1
              safety and tolerability of ibuprofen                                claims
              compared with paracetamol in pediatric
              pain and fever [123]
              93. 2009: Online survey of anesthetists         NA: Survey          Makes no safety        NA: Survey        1
              and the current prescribing practice of i.v.                        claims
              paracetamol [124]
              94: 2010: Hemodynamic study with                72 neonates, age    Assessment of          6 hours           1
              intravenous paracetamol in neonates [125]       1 to 27 days;       hemodynamics. No
                                                              average age is 3    safety claims
                                                              days                made.
              95: 2010: Review describing post-               NA: Review          Makes no safety        NA: Review        1
              operative pain management [126]                                     claim
              96: 2010: Meta-analysis of efficacy and         NA: Review          Claims similar         NA: Review        1
              safety of ibuprofen and paracetamol in                              safety profiles
              children and adults [127]                                           between
                                                                                  paracetamol and
                                                                                  ibuprofen, but
                                                                                  makes no absolute
                                                                                  safety claim
              97: 2011: Study of efficacy and safety in       NA: study in        NA: study in adults    NA: study in      1
              adults [128]                                    adults                                     adults
              98: 2011: Literature review of clinical         NA: Review          Claims: it “has        NA: Review        1
              trials of intravenous paracetamol for                               been well known
              postoperative pain [129]                                            as a safe and
                                                                                  effective” without
                                                                                  citation
              99: 2012: Review of efficacy and                NA: Review          Makes no safety        NA: Review        1
              pharmacokinetics of paracetamol in                                  claims
              pediatric patients [130]
              100: 2012: Retrospective study using data       230 patients,       Postoperative fever    1 year            1
              collected on pediatric surgery patients to      age 0 to 15         and its etiologies,
              identify the status and risk factors of major   years, average      mortality
              infections [24]                                 age is 4.28 years   discharge, and
                                                                                  rates of re-open
                                                                                  sternotomy
                                                                                  reintubation

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              101. 2013: Case series evaluating the           10 preterm           Pre- and               3 days              1
              efficacy of intravenous paracetamol in          infants, age 2 to    posttreatment
              preterm infants with hemodynamically            15 days              levels of liver
              significant patent ductus arteriosus                                 enzymes
              (hsPDA) [131]
              102. 2013: Mechanistic study in                 NA: Study in         Makes no safety        NA: Study in        1
              laboratory animals [132]                        laboratory           claim                  laboratory
                                                              animals                                     animals
              103. 2014. Literature review assessing          NA: Review           Claims: “doses of      NA: Review          1
              liver toxicity due to paracetamol in                                 less than 75
              children [133]                                                       mg/kg/day of
                                                                                   paracetamol are
                                                                                   safe for children
                                                                                   younger than 6
                                                                                   years of age”
                                                                                   without citation

                 Several studies emerged as popular citations for the claim that paracetamol use in infants or children is safe
             when used as directed. Only 19 articles were cited more than twice, and the most popular article [22] was cited a
             total of 13 times (Table 2) by the 218 articles we identified. However, in some cases, well cited articles did not make
             original claims of safety, and are therefore not included in Table 2. For example, an article by Perrott and colleagues
             in 2004 [23] was cited a total of 7 total times by the 218 articles we identified. However, Perrott’s article, being a
             review, does not make original claims of safety, but rather cites additional articles as the authority for assurance of
             safety (Figure 1). Thus, Perrott’s article is not included in Table 2 as an original source for the claim that use of
             paracetamol is safe for infants and children when used as directed.

                 Of the 103 articles cited as authority for the safety of paracetamol use in infants or children, 27 did not make
             claims of safety and did not address safety experimentally (Table 2). Thus, 76 of the 103 articles did address safety,
             and 48 of these (63%) had already been identified in the original 218 articles culled from the Medline search. Of the
             103 articles, 36 articles described experimental studies which involved paracetamol use in infants or children.
             Although several of these studies provided measures of liver function (Table 2), none of these 36 studies provided
             any assessment of neuropsychiatric function. Further, the median follow-up time of all 36 studies was 24 hours
             (Figure 2), far too short to identify any long-term effects of drug exposure on neuropsychiatric function. Four
             studies had a follow-up time of longer than 10 days, with one study in particular [24] evaluating patients out to one
             year. However, these studies were blind to any potential effects of drug exposure on long-term neuropsychiatric
             function. For example, although patients were followed for a full year in one study [24], the only endpoint measured
             was re-admission for surgery.

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                 Figure 2. Maximum follow-up times for 34 of the 36 studies describing experiments designed to test the safety
             of acetaminophen in infants or children. One study [24] monitoring readmission for surgery for one year is omitted
             from the graph. Another study [66] observing patients during their inpatient visit did not specify duration of
             monitoring, and therefore could not be included in the graph. The three studies monitoring outcomes for 4 weeks
             (shown on the graph) did not monitor neuropsychiatric function.

                      The path from more recent papers to the original research addressing the safety of paracetamol in infants
             and children was sometimes convoluted. In one notable case, a popular citation did not did appear the literature
             (Table 2). Not only did the volume and journal number not match, but the title could not be found elsewhere. As
             another example, the citations reporting safety of paracetamol use in children reported by Temple and colleagues in
             2017 [25] are illustrated in Figure 1. This article provides a detailed description of three prior reports to the
             European Medicines Agency (reports 24570, 24571, and 47402) which, together, according to the authors, “confirm
             that the recommended standard paracetamol dose of 10 to 15 mg/kg is a safe and effective dose for use in pediatric
             patients when administered as a single dose or as multiple doses for up to 72 hours.” However, the only safety
             measure used in the three studies was ALT levels as a marker for liver function, assessed for a maximum of 72
             hours. In addition to the three reports described in their publication, Temple and colleagues cite 10 additional
             articles as sources for safety, including the claim that paracetamol has a “well-established efficacy and favorable
             safety profile” (Figure 1). Among these 10 papers is a clinical trial [26] that addresses efficacy but not safety, and
             refers to two other papers that address safety, one by Lesko [22]. The paper by Lesko contradicts the view that
             paracetamol is safe, finding that paracetamol is significantly worse than ibuprofen in terms of risk for outpatient
             visits following treatment of children with asthma. Another of the articles cited by Temple in 2017, a review written
             by Temple more than 30 years before [27], cites a paper in the Federal Register [28] as the source for the statement

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             that “Paracetamol is relatively free of side effects and has a wide margin of safety between therapeutic doses and
             toxic doses.” The document in the Federal Register [28], a lengthy treatise primarily focused on determination of the
             appropriate dose for adults of salicylates in general and aspirin in particular, in turn cites two papers involving safety
             studies of paracetamol in the human pediatric population. One of those studies [29] evaluated 98 children using a
             blinded approach comparing aspirin and paracetamol, and monitored the children for only 6 hours. The other study
             [30] monitored 20 children following administration of both aspirin and paracetamol. In that study, monitoring
             occurred for 6 hours or less and no information was provided regarding particular side effects that were being
             assessed. Importantly, the Federal Register [28] attributed their view that paracetamol has “a wide range of safety”
             to laboratory animal studies showing that the lethal dose of paracetamol is significantly greater than the dose
             administered to humans. Unfortunately, studies had not been conducted at that time showing that paracetamol
             induces permanent neurodevelopmental injury in laboratory animals at far lower doses than the lethal dose [15, 16],
             similar to doses administered to infants and children.

             Discussion:

                  Our initial search of the PubMed® Database and review of more than 3000 titles and abstracts yielded 218
             papers making claims that paracetamol is safe for infants and children when used as directed. Claims of safety in
             those 218 papers were traced back to 103 articles shown in Table 2, but less than 20 of those were cited more than
             twice, indicating that a limited number of studies are considered key or cornerstone to the view that paracetamol is
             safe for use in infants or children.

                  This study confirms the view that paracetamol use in infants and children is widely thought to be safe when
             used as directed, without reservations or caveats. The fact that 27 out of 103 citations did not, in fact, demonstrate
             safety or make safety claims might suggest that the safety of paracetamol is taken for granted, and is not carefully
             considered. This view is supported by the observation that one popular citation for safety does not exist in the
             literature.

                  Despite apparently being taken for granted, this study demonstrates that the drug was never shown to be safe for
             neurodevelopment. This conclusion is consistent with emerging studies showing a connection between paracetamol
             use during development and long term neuropsychiatric disfunction as described in the Introduction. This conclusion
             is also consistent with emerging studies in animal models showing exquisite sensitivity of long-term behavior to
             early life exposure to paracetamol at near-therapeutic doses.

                  Although not the intended purpose of this systematic review, it demonstrated that paracetamol has been proven
             safe for liver function in infants and in small children, even at doses higher than those currently recommended.
             During the course of this review, an assumption was repeatedly encountered: because the target of paracetamol
             toxicity in adults is the liver, demonstration of safety in infants and children need only be tested in the liver. This
             assumption was/is held despite the fact that the target tissue for drug function is in the central nervous system, not
             the liver. A similar assumption has proven tragically fatal in the past, when it was assumed that metabolism of the

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             antibiotic chloramphenicol was the same in infants as in adults. In that case, administration of the drug in infants led
             to a number of deaths [31-33] before the problem was identified.

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